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New Genetic Mutation Identified: the Most Common Cause of FTD and ALS Accounting for as Much as One Third of All Familial ALS

September 21, 2011

Two independent studies, both funded by The ALS Association, have found a genetic abnormality that, according to researchers, is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As reported in the recent online issue of the scientific journal Neuron, an unusual mutation was discovered, where a short DNA sequence is repeated many more times as compared to healthy individuals.

Using next generation sequencing in a study led by Bryan J. Traynor, M.D., Laboratory of Neurogenetics, National Institute on Aging, the team identified a GGGGCC hexanucleotide repeat within the non-coding region of a gene on chromosome 9p21. This repeat accounts for nearly 50% of familial ALS cases in Finland and more than a third of familial cases in other European populations.

The identification of the same genetic abnormality was independently made by a group at Mayo Clinic in Jacksonville, Florida led by Rosa Rademakers, Ph.D. and published in the same journal. The repeat of C and G (two of the four nucleotides that make up the genetic code) was found in a non-coding region of a gene called C9ORF72, which has no known function and its role in disease remains a mystery.

“We believe that when the defective gene is transcribed into a messenger RNA molecule, the expanded repeat section causes the RNA to bind tightly to certain proteins, forming clumps within the brain cells,” according to Dr. Rademakers. “By binding these proteins, the abnormal RNA may prevent these proteins from carrying out their normal functions in the cell.”

The identification of the genetic lesion on the chromosome 9p21 locus marks a major milestone in ALS research. Several studies have led to the identification of this region linked to chromosome 9p21 including recent genome-wide association (GWA) studies (visit http://www.alsa.org/news/archive/genome-study-identifies-link.html to read a report).

Investigators worldwide have been committed to identifying the gene alteration, and until now it had remained elusive. This hexanucleotide repeat was identified using state of the art next-generation sequencing technology. “The repeat expansion was highly associated with ALS and FTD in the Finnish population,” said Dr. Traynor.

“Since all routine methods of genetic analysis had failed to find the genetic defect in this region, we suspected the defect could be a rare DNA repeat expansion,” said lead investigator Mariely DeJesus-Hernandez from the Mayo Clinic-led research team. This team found an area of DNA that in healthy individuals is normally repeated only 2 to 23 times, but in ALS or FTD patients is repeated 700-1,600 times. These changes were found in almost 12 percent of familial FTD and more than 23 percent of familial ALS samples studied at Mayo Clinic.

The defect is also the strongest genetic risk factor found to date for the more common, non-inherited, sporadic forms of these diseases. It was found in 3 percent of sporadic FTD and 4 percent of sporadic ALS samples in Mayo Clinic’s large clinical patient series.

“This finding has the potential to lead to significant insights into how both of these neurodegenerative diseases develop, and may give us much needed leads into new ways to treat our patients,” said Senior Investigator Rosa Rademakers, a neuroscientist at the Mayo Clinic campus in Florida.

The repeat expansion is more than twice as common as the SOD1 gene in familial ALS and four times as common as TDP43, FUS, VCP combined. The identification of this repeat and the rapid, reliable method of screening individuals for repeat expansion may have immediate utility by allowing early identification of ALS patients at risk of cognitive impairment and FTD cases at risk of progressive paralysis.

In the long term, the identification of the genetic lesions underlying the chromosome 9p21 ALS-FTD together with the high frequency makes it an ideal target for drug development aimed at ameliorating the disease process. “Whether the pathogenic process is linked to a loss of function in which the expansion disrupts splicing of the target or through the generation of toxic RNA disrupting normal cellular processes will be determined by further study,” added Traynor. “However the large size of the expansion and its location in a non-coding region may argue for the later mechanism.”

Disruption of RNA metabolism has already been identified as an important mechanism in those cases with TDP43 and FUS mutations, and this discovery provides further evidence for disrupted RNA metabolism as a key underlying cause of disease.

“This is tremendously exciting,” commented ALS Association Chief Scientist Dr. Lucie Bruijn, Ph.D. “These findings will significantly impact the field as we begin to understand more about the consequence of these changes to the disease process, aid our understanding of FTD and ALS, potentially provide a diagnostic tool, and enable the development of new therapeutic approaches.”

Dr. Traynor’s team was funded by The ALS Association’s Abendroth ALS Genetic Discovery Fund, with additional funding from the Robert Packard Institute of ALS Research at Johns Hopkins. Dr. Rademakers’ team was funded by the The ALS Association’s Florida Chapter and Richard Essey. Both studies were funded by the National Institute on Aging and the National Institute on Neurological Diseases and Stroke.